Journal Articles

High-Resolution Genetic Mapping in the Diversity Outbred Mouse Population Identifies Apobec1 as a Candidate Gene for Atherosclerosis

October 23, 2014

High-Resolution Genetic Mapping in the Diversity Outbred Mouse Population Identifies Apobec1 as a Candidate Gene for Atherosclerosis G3 (Bethesda). 2014 Oct 23, Smallwood TL1, Gatti DM2, Quizon P3, Weinstock GM4, Jung KC1, Zhao L1, Hua K1, Pomp D1, Bennett BJ5.

  • University of North Carolina at Chapel Hill;
  • 2The Jackson Laboratory;
  • 3University of North Carolina Nutrition Research Institute;
  • 4Jackson Laboratory for Genomic Medicine;
  • 5University of North Carolina at Chapel Hill; UNC Nutrition Research Institute bennettb@email.unc.edu.

Abstract

Inbred mice exhibit strain-specific variation in susceptibility to atherosclerosis and dyslipidemia which renders them useful in dissecting the geneticarchitecture of these complex diseases. Traditional quantitative trait locus (QTL) mapping studies using inbred strains often identify large genomic regions, containing many genes, due to limited recombination and/or sample size. This hampers candidate gene identification and translation of these results into possible risk factors and therapeutic targets. An alternative approach is the use of multi-parental outbred lines for genetic mapping, such as the Diversity Outbred (DO) mouse panel, which can be more informative than traditional two-parent crosses and can aid in the identification of causal genes and variants associated with QTL. We fed 292 female DO mice either a high-fat, cholesterol-containing (HFCA) diet, to induceatherosclerosis, or a low-fat, high-protein diet for 18 weeks and measured plasma lipid levels before and after diet treatment. We measured markers of atherosclerosis in the mice fed the HFCA diet. The mice were genotyped on a medium density SNP array and founder haplotypes were reconstructed using a hidden Markov model. The reconstructed haplotypes were then used to perform linkage mapping of atherosclerotic lesion size as well as plasma total cholesterol, triglycerides, insulin, and glucose. Among our highly significant QTL we detected a ~100 kb QTL interval foratherosclerosis on Chromosome 6, as well as a 1.4 Mb QTL interval on Chromosome 9 for triglyceride levels at baseline and a coincident 22.2 Mb QTL interval on Chromosome 9 for total cholesterol after dietary treatment. One candidate gene within the Chromosome 6 peak region associated with atherosclerosis is Apobec1, the apolipoprotein B (ApoB) mRNA editing enzyme, which plays a role in the regulation of ApoB, a critical component of LDL, by editing ApoB mRNA. This study demonstrates the value of the DO population to improve mapping resolution and to aid in the identification of potential therapeutic targets for cardiovascular disease. Using a DO mouse population fed a HFCA diet we were able to identify an A/J-specific isoform of Apobec1 that contributes to atherosclerosis.

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